Currently, the prevalence of diabetes mellitus is at an epidemic proportion in the general population and is associated with excessive cardiovascular morbidity and mortality. In particular, both impaired insulin secretion and resistance contribute to the development of the disease, particularly Type 2 diabetes mellitus. The drug class known as thiazolidinediones (TZDs) has been shown to improve whole body insulin sensitivity. The beneficial effects of TZDs are attributed to the activation of the nuclear receptor class of transcription factors known as PPAR (Peroxisomal Proliferator Activating Receptor). The PPAR family of nuclear receptors includes three members (PPARα, PPARβ/δ, and PPARγ) that are highly conserved in mammals, each forming a functional heterodimeric complex with 9-cis retinoic acid receptor (RXR).
However, currently available TZDs are associated with adverse cardiovascular events mostly due to development of peripheral edema and weight gain. For example, a full PPARγ agonist (rosiglitazone) has been shown to increase the risk of adverse cardiovascular events, in part due to the increase in fluid retention. Rosiglitazone is known to bind in the ligand binding domain (AF2 domain) of the PPAR-gamma receptor. This ligand interacts with many amino acids that confer bioactivity, especially His 449 and Tyr 443. It has been determined that Tyr 473 induces the increase in adipocyte maturation, including lipid accumulation and storage. However, strong interaction with this site also has led to unwanted off target effects including increased sodium retention in the kidneys, increased edema, ectopic fat accumulation in the heart, liver and muscle including skeletal muscle and heart. Therefore, the full agonist activity at PPARγ is believed to be associated with the deleterious side effects observed following treatment with TZDs such as rosiglitazone and pioglitazone.
PPARβ/δ activation is associated with improving overall circulating cholesterol levels (HDL, LDL, and triglycerides) and is ubiquitously expressed throughout the body. Furthermore, overexpression of PPARβ/δ in skeletal muscle improves the glycolytic muscle fiber type in animal models and thus improves circulating glucose and fatty acid levels. However, agonists for this class of receptors do not have a significant impact upon improving insulin sensitivity.
Therefore, there exists a need for new compounds such as new TZDs that can effectively treat diabetes mellitus. Because diabetes and metabolic syndrome are associated with defects in glucose oxidation and lipid metabolism, the development of dual agonists that can activate both PPARβ/δ and PPARγ simultaneously is highly desirable. Accordingly, the present disclosure provides novel compounds with activity as PPARβ/δ and PPARγ dual agonists which exhibit desirable properties and provide related advantages for improvement in the treatment of diabetes mellitus.
Furthermore, Alzheimer's disease (AD) is one the fifth leading causes of death amongst people over 65 years and over in the United States, illustrating the limitations of the current therapies to prevent the progression of the disease. Continuous increase in the mortality rates due to AD indicates the critical need for new drug discovery based upon discovery of novel molecular targets for therapeutic potential. In particular, possible novel molecular targets correlations between Type 2 diabetes mellitus and AD have been found to have direct pathological links. Moreover, the epidemic proportions of Type 2 diabetes mellitus highlights the contribution of diabetes to the development of AD. Although there are direct links between AD and diabetes in the manifestation of cognitive impairment, there is a lack of vital knowledge to understanding how impaired insulin signaling directly alters memory in AD.
It is well known that PPARs are centrally involved in regulating whole body insulin sensitivity and may serve as a potential therapeutic target for AD. Pharmacological activation of PPARs has been shown to improve pathologies as well as learning and memory in transgenic AD animal models. However, there exists a need to provide insights into the molecular signaling mechanisms mediated by central (hippocampal) PPAR activation and improved cognition in AD.
Recently, ligand based activation of the nuclear receptor PPARγ has been shown to improve cognition in AD patients and transgenic animal models of AD by attenuating amyloid beta levels and Tau hyperphosphorylation. However, the use of TZDs for AD is limited due to their poor blood-brain barrier (BBB) permeability and undesirable side effects. Pioglitazone (a PPARγ agonist) and rosiglitazone (a full PPARγ agonist) were initially characterized as BBB impermeable, thus requiring high dose treatment over an extended period of time to obtain a significant therapeutic effect. However, long term treatment of high doses of rosiglitazone lead to life threatening side effects in humans. Therefore, there exists a need for development of TZDs with potential application as a treatment for AD. Accordingly, the present disclosure provides novel compounds with activity as PPARβ/δ and PPARγ dual agonists which exhibit desirable properties and provide related advantages for improvement in the treatment of AD.
The present disclosure provides novel compounds with activity as PPARβ/δ and PPARγ dual agonists. The disclosure also provides methods of treating diabetes mellitus and methods of treating Alzheimer's disease utilizing the novel compounds, as well as pharmaceutical formulations comprising the novel compounds.
The novel compounds, pharmaceutical formulations, and methods comprising the novel compounds according to the present disclosure provide several advantages compared to other compositions, formulations, and methods known in the art. First, the novel compounds have strong binding affinity for both PPARγ and PPARβ/δ. Second, the novel compounds demonstrate increased gene expression of mitochondrial markers in skeletal muscle cells, as well as increased mRNA expression levels of advantageous PPARγ targets. Third, the novel compounds have increased BBB permeability, leading to enhanced CNS activity that is essential for potential treatment in Alzheimer's disease. Finally, the novel compounds have not been associated with adverse nonspecific side effects (e.g., ectopic lipid accumulation and hemodynamic effects resulting in increased incidences of myocardial infarctions) that have been observed with other TZDs known in the art.
The following numbered embodiments are contemplated and are non-limiting:
1. A composition comprising a compound selected from the group consisting of

or a pharmaceutically acceptable salt or derivative thereof.
2. A composition comprising a compound of the formula

or a pharmaceutically acceptable salt thereof, wherein
B is a bond or (CH2)X where x is 1, 2, 3, or 4;
n is 1, 2, or 3;
R is C1-C6 alkyl or hydrogen;
RA represents from 1 to 4 substituents independently selected in each instance from the group consisting of F and CF3; and
RB is C1-C6 alkyl, F, Cl, Br, CN, or CF3.
3. A composition comprising a compound selected from the group consisting of

4. The composition of any of the above clauses, wherein the compound is an agonist of a PPARγ receptor.
5. The composition of any of the above clauses, wherein the compound has a binding affinity for the PPARγ receptor between −10.0 and −12.0 kcal/mol.
6. The composition of any of the above clauses, wherein the compound binds with an amino acid residue of the PPARγ receptor binding pocket, and wherein the amino acid residue is selected from the group consisting of Cys285, Thr288, Thr289, Leu330, Val334, Leu339, Leu353, and Phe368.
7. The composition of any of the above clauses, wherein the binding between the compound and the amino acid residue is a hydrogen bond.
8. The composition of any of the above clauses, wherein the compound is an agonist of a PPARγ receptor.
9. The composition of any of the above clauses, wherein the compound has a binding affinity for the PPARγ receptor between −10.0 and −12.0 kcal/mol.
10. The composition of any of the above clauses, wherein the compound binds with an amino acid residue of the PPARγ receptor binding pocket, and wherein the amino acid residue is selected from the group consisting of Leu228, Cys285, Gln286, Arg288, Ser289, Glu295, Met329, Leu330, Ser342, Glu343, Phe363, and His 449.
11. The composition of any of the above clauses, wherein the binding between the compound and the amino acid residue is a hydrogen bond.
12. The composition of any of the above clauses, wherein the compound is an agonist of PPARδ and an agonist of PPARγ
13. The composition of any of the above clauses, wherein the compound permeates the blood-brain barrier.
14. A pharmaceutical formulation comprising a therapeutically effective amount of a compound selected from the group consisting of
or a pharmaceutically acceptable salt or derivative thereof, and one or more pharmaceutically acceptable carriers.
15. A pharmaceutical formulation comprising a therapeutically effective amount of a compound of the formula

or a pharmaceutically acceptable salt thereof, wherein
B is a bond or (CH2)X where x is 1, 2, 3, or 4;
n is 1, 2, or 3;
R is C1-C6 alkyl or hydrogen;
RA represents from 1 to 4 substituents independently selected in each instance from the group consisting of F and CF3; and
RB is C1-C6 alkyl, F, Cl, Br, CN, or CF, and one or more pharmaceutically acceptable carriers.
16. A pharmaceutical formulation comprising a therapeutically effective amount of a compound selected from the group consisting of

or a pharmaceutically acceptable salt or derivative thereof, and one or more pharmaceutically acceptable carriers.
17. The pharmaceutical formulation of any of the above clauses further comprising at least one additional active ingredient.
18. The pharmaceutical formulation of any of the above clauses, wherein the compound is an agonist of a PPARδ receptor.
19. The pharmaceutical formulation of any of the above clauses, wherein the compound has a binding affinity for the PPARδ receptor between −10.0 and −12.0 kcal/mol.
20. The pharmaceutical formulation of any of the above clauses, wherein the compound binds with an amino acid residue of the PPARδ receptor binding pocket, and wherein the amino acid residue is selected from the group consisting of Cys285, Thr288, Thr289, Leu330, Val334, Leu339, Leu353, and Phe368.
21. The pharmaceutical formulation of any of the above clauses, wherein the binding between the compound and the amino acid residue is a hydrogen bond.
22. The pharmaceutical formulation of any of the above clauses, wherein the compound is an agonist of a PPARγ receptor.
23. The pharmaceutical formulation of any of the above clauses, wherein the compound has a binding affinity for the PPARγ receptor between −10.0 and −12.0 kcal/mol.
24. The pharmaceutical formulation of any of the above clauses, wherein the compound binds with an amino acid residue of the PPARγ receptor binding pocket, and wherein the amino acid residue is selected from the group consisting of Leu228, Cys285, Gln286, Arg288, Ser289, Glu295, Met329, Leu330, Ser342, Glu343, Phe363, and His 449.
25. The pharmaceutical formulation of any of the above clauses, wherein the binding between the compound and the amino acid residue is a hydrogen bond.
26. The pharmaceutical formulation of any of the above clauses, wherein the compound is an agonist of PPARγ and an agonist of PPARγ.
27. The pharmaceutical formulation of any of the above clauses, wherein the compound permeates the blood-brain barrier.
28. A method of treating diabetes mellitus in a patient in need thereof, said method comprising the step of administering a therapeutically effective amount of a composition to the patient, wherein the composition comprises a compound selected from the group consisting of

or a pharmaceutically acceptable salt or derivative thereof, and wherein the administration results in improvement of at least one symptom associated with diabetes mellitus in the patient.
29. A method of treating diabetes mellitus in a patient in need thereof, said method comprising the step of administering a therapeutically effective amount of a composition to the patient, wherein the composition comprises a compound of the formula

or a pharmaceutically acceptable salt thereof, wherein
B is a bond or (CH2)X where x is 1, 2, 3, or 4;
n is 1, 2, or 3;
R is C1-C6 alkyl or hydrogen;
RA represents from 1 to 4 substituents independently selected in each instance from the group consisting of F and CF3; and
RB is C1-C6 alkyl, F, Cl, Br, CN, or CF3, and wherein the administration results in improvement of at least one symptom associated with diabetes mellitus in the patient.
30. A method of treating diabetes mellitus in a patient in need thereof, said method comprising the step of administering a therapeutically effective amount of a composition to the patient, wherein the composition comprises a compound selected from the group consisting of
or a pharmaceutically acceptable salt or derivative thereof, and wherein the administration results in improvement of at least one symptom associated with diabetes mellitus in the patient.
31. A method of improving insulin sensitivity in a patient, said method comprising the step of administering a therapeutically effective amount of a composition to the patient, wherein the composition comprises a compound selected from the group consisting of

or a pharmaceutically acceptable salt or derivative thereof, and wherein the administration results in an increase in insulin sensitivity in the patient.
32. A method of improving insulin sensitivity in a patient, said method comprising the step of administering a therapeutically effective amount of a composition to the patient, wherein the composition comprises a compound of the formula

or a pharmaceutically acceptable salt thereof, wherein
B is a bond or (CH2)X where x is 1, 2, 3, or 4;
n is 1, 2, or 3;
R is C1-C6 alkyl or hydrogen;
RA represents from 1 to 4 substituents independently selected in each instance from the group consisting of F and CF3; and
RB is C1-C6 alkyl, F, Cl, Br, CN, or CF3, and wherein the administration results in an increase in insulin sensitivity in the patient.
33. A method of improving insulin sensitivity in a patient, said method comprising the step of administering a therapeutically effective amount of a composition to the patient, wherein the composition comprises a compound selected from the group consisting of
or a pharmaceutically acceptable salt or derivative thereof, and wherein the administration results in an increase in insulin sensitivity in the patient.
34. A method of improving glucose utilization in a patient, said method comprising the step of administering a therapeutically effective amount of a composition to the patient, wherein the composition comprises a compound selected from the group consisting of

or a pharmaceutically acceptable salt or derivative thereof, and wherein the administration results in an increase in glucose utilization in the patient.
35. A method of improving glucose utilization in a patient, said method comprising the step of administering a therapeutically effective amount of a composition to the patient, wherein the composition comprises a compound of the formula

or a pharmaceutically acceptable salt thereof, wherein
B is a bond or (CH2)X where x is 1, 2, 3, or 4;
n is 1, 2, or 3;
R is C1-C6 alkyl or hydrogen;
RA represents from 1 to 4 substituents independently selected in each instance from the group consisting of F and CF3; and
RB is C1-C6 alkyl, F, Cl, Br, CN, or CF3, and
wherein the administration results in an increase in glucose utilization in the patient.
36. A method of improving glucose utilization in a patient, said method comprising the step of administering a therapeutically effective amount of a composition to the patient, wherein the composition comprises a compound selected from the group consisting of
or a pharmaceutically acceptable salt or derivative thereof, and wherein the administration results in an increase in glucose utilization in the patient.
37. A method of treating Alzheimer's disease in a patient in need thereof, said method comprising the step of administering a therapeutically effective amount of a composition to the patient, wherein the composition comprises a compound selected from the group consisting of

or a pharmaceutically acceptable salt or derivative thereof, and wherein the administration results in improvement of at least one symptom associated with Alzheimer's disease in the patient.
38. A method of treating Alzheimer's disease in a patient in need thereof, said method comprising the step of administering a therapeutically effective amount of a composition to the patient, wherein the composition comprises a compound of the formula

or a pharmaceutically acceptable salt thereof, wherein
B is a bond or (CH2)X where x is 1, 2, 3, or 4;
n is 1, 2, or 3;
R is C1-C6 alkyl or hydrogen;
RA represents from 1 to 4 substituents independently selected in each instance from the group consisting of F and CF3; and
RB is C1-C6 alkyl, F, Cl, Br, CN, or CF3, and wherein the administration results in improvement of at least one symptom associated with Alzheimer's disease in the patient.
39. A method of treating Alzheimer's disease in a patient in need thereof, said method comprising the step of administering a therapeutically effective amount of a composition to the patient, wherein the composition comprises a compound selected from the group consisting of
or a pharmaceutically acceptable salt or derivative thereof, and wherein the administration results in improvement of at least one symptom associated with Alzheimer's disease in the patient.
40. A method of improving a cognitive deficit in a patient, said method comprising the step of administering a therapeutically effective amount of a composition to the patient, wherein the composition comprises a compound selected from the group consisting of

or a pharmaceutically acceptable salt or derivative thereof, and wherein the administration results in an improvement in a cognitive deficit in the patient.
41. A method of improving a cognitive deficit in a patient, said method comprising the step of administering a therapeutically effective amount of a composition to the patient, wherein the composition comprises a compound of the formula

or a pharmaceutically acceptable salt thereof, wherein
B is a bond or (CH2)X where x is 1, 2, 3, or 4;
n is 1, 2, or 3;
R is C1-C6 alkyl or hydrogen;
RA represents from 1 to 4 substituents independently selected in each instance from the group consisting of F and CF3; and
RB is C1-C6 alkyl, F, Cl, Br, CN, or CF3, and wherein the administration results in an improvement in a cognitive deficit in the patient
42. A method of improving a cognitive deficit in a patient, said method comprising the step of administering a therapeutically effective amount of a composition to the patient, wherein the composition comprises a compound selected from the group consisting of
or a pharmaceutically acceptable salt or derivative thereof, and wherein the administration results in an improvement in a cognitive deficit in the patient.
43. The method of any of the above clauses, wherein the method is associated with improved insulin sensitivity in the patient.
44. The method of any of the above clauses, wherein the method is associated with improved glucose utilization in the patient.
45. The method of any of the above clauses, wherein the method is associated with improved induction of mitochondrial biogenesis in the patient.
46. The method of any of the above clauses, wherein the method is associated with improved insulin signaling in the brain of the patient.
47. The method of any of the above clauses, wherein the method is not associated with lipid accumulation in the patient.
48. The method of any of the above clauses, wherein the lipid accumulation is ectopic lipid accumulation.
49. The method of any of the above clauses, wherein the method is not associated with adverse cardiovascular event in the patient.
50. The method of any of the above clauses, wherein the adverse cardiovascular event is heart failure.
51. The method of any of the above clauses, wherein the adverse cardiovascular event is a myocardial infarction.
52. The method of any of the above clauses, wherein the method does not induce an increase in lipid accumulation in the patient.
53. The method of any of the above clauses, wherein the lipid accumulation is ectopic lipid accumulation.
54. The method of any of the above clauses, wherein the diabetes mellitus is Type 1 diabetes mellitus.
55. The method of any of the above clauses, wherein the diabetes mellitus is Type 2 diabetes mellitus.
56. The method of any of the above clauses, wherein the method is associated with improvement of a cognitive deficit in the patient.
57. The method of any of the above clauses, wherein the cognitive deficit is memory impairment.
58. The method of any of the above clauses, wherein the method is associated with an improvement in cognition in the patient.
59. The method of any of the above clauses, wherein the method is associated with central PPARγ activation.
60. The method of any of the above clauses, wherein the central PPARγ activation is in the hippocampus of the patient.
61. The method of any of the above clauses, wherein the method is associated with an improvement in synaptic plasticity in the patient.
62. The method of any of the above clauses, wherein the method is associated with a decrease in Tau phosphorylation in the hippocampus of the patient.
63. The method of any of the above clauses, wherein the method is associated with a decrease in PTEN expression in the hippocampus of the patient.
64. The method of any of the above clauses, wherein the method is associated with an increase in BDNF expression in the hippocampus of the patient.
65. The method of any of the above clauses, wherein the method is associated with improved insulin sensitivity in the patient.
66. The method of any of the above clauses, wherein the method is associated with improved glucose utilization in the patient.
67. The method of any of the above clauses, wherein the method is associated with improved induction of mitochondrial biogenesis in the patient.
68. The method of any of the above clauses, wherein the method is associated with improved insulin signaling in the brain of the patient.
69. The method of any of the above clauses, wherein the method is not associated with lipid accumulation in the patient.
70. The method of any of the above clauses, wherein the lipid accumulation is ectopic lipid accumulation.
71. The method of any of the above clauses, wherein the method is not associated with adverse cardiovascular event in the patient.
72. The method of any of the above clauses, wherein the adverse cardiovascular event is heart failure.
73. The method of any of the above clauses, wherein the adverse cardiovascular event is a myocardial infarction.
74. The method of any of the above clauses, wherein the method does not induce an increase in lipid accumulation in the patient.
75. The method of any of the above clauses, wherein the lipid accumulation is ectopic lipid accumulation.
Various embodiments of the invention are described herein as follows. In one embodiment described herein, a composition is provided. The composition comprises a compound selected from the group consisting of

or a pharmaceutically acceptable salt or derivative thereof.
In other embodiments described herein, a composition is provided of the formula

or a pharmaceutically acceptable salt thereof, wherein
B is a bond or (CH2)X where x is 1, 2, 3, or 4;
n is 1, 2, or 3;
R is C1-C6 alkyl or hydrogen;
RA represents from 1 to 4 substituents independently selected in each instance from the group consisting of F and CF3; and
RB is C1-C6 alkyl, F, Cl, Br, CN, or CF3.
In various embodiment described herein, another composition is provided. The composition comprises a compound selected from the group consisting of

or a pharmaceutically acceptable salt or derivative thereof. Such compounds can be made according to known processes in the art.
In other embodiments, a pharmaceutical formulation is provided. The pharmaceutical formulation comprises a therapeutically effective amount of a compound of any of the described compounds or formulas described herein, or a pharmaceutically acceptable salt or derivative thereof, and one or more pharmaceutically acceptable carriers.
In other embodiments, a method of treating diabetes mellitus in a patient in need thereof is provided. The method comprises the step of administering a composition to the patient, wherein the composition comprises a compound of any of the described compounds or formulas described herein, or a pharmaceutically acceptable salt or derivative thereof, and wherein the administration results in improvement of at least one symptom associated with diabetes mellitus in the patient.
In yet other embodiments, a method of treating Alzheimer's disease in a patient in need thereof is provided. The method comprises the step of administering a composition to the patient, wherein the composition comprises a compound of any of the described compounds or formulas described herein, or a pharmaceutically acceptable salt or derivative thereof, and wherein the administration results in improvement of at least one symptom associated with Alzheimer's disease in the patient.
In yet other embodiments, a method of improving insulin sensitivity in a patient is provided. The method comprises the step of administering a composition to the patient, wherein the composition comprises a compound of any of the described compounds or formulas described herein, or a pharmaceutically acceptable salt or derivative thereof, and wherein the administration results in an increase in insulin sensitivity in the patient.
In other embodiments, a method of improving glucose utilization in a patient is provided. The method comprises the step of administering a composition to the patient, wherein the composition comprises a compound of any of the described compounds or formulas described herein, or a pharmaceutically acceptable salt or derivative thereof, and wherein the administration results in an increase in glucose utilization in the patient.
In yet other embodiments, a method of improving a cognitive deficit in a patient is provided. The method comprises the step of administering a composition to the patient, wherein the composition comprises a compound of any of the described compounds or formulas described herein, or a pharmaceutically acceptable salt or derivative thereof, and wherein the administration results in an improvement in a cognitive deficit in the patient.
In various aspects, the compounds of the present disclosure are compounds of the following chemical structures:

For ease of reference, the compounds of the above structures may be referred to herein as “Compound 9,” “Compound 3-91,” “Compound 4-23,” and “Compound 3-121,” respectively. It will be understood that, in the practice of the present disclosure, reference to “Compound 9” means Compound 9, pharmaceutically acceptable salts thereof, or derivatives thereof. The same nomenclature applies to “Compound 3-91,” “Compound 4-23,” and “Compound 3-121.” Furthermore, the same nomenclature applies to any of the other compounds described herein.
Pharmaceutically acceptable salts, and common methodology for preparing them, are known in the art. See, e.g., P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2002); S. M. Berge, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.
In other aspects, the compounds of the present disclosure are of the formula

or a pharmaceutically acceptable salt thereof, wherein
B is a bond or (CH2)X where x is 1, 2, 3, or 4;
n is 1, 2, or 3;
R is C1-C6 alkyl or hydrogen;
RA represents from 1 to 4 substituents independently selected in each instance from the group consisting of F and CF3; and
RB is C1-C6 alkyl, F, Cl, Br, CN, or CF3.
As used herein, the term “alkyl” includes a chain of carbon atoms, which is optionally branched. Illustrative alkyl groups are, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, and the like.
In each of the foregoing and each of the following embodiments, it is to be understood that the formulae include and represent not only all pharmaceutically acceptable salts of the compounds, but also include any and all hydrates and/or solvates of the compound formulae. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and/or coordination compounds with water and/or various solvents, in the various physical forms of the compounds. Accordingly, the above formulae are to be understood to be a description of such hydrates and/or solvates, including pharmaceutically acceptable solvates.
In each of the foregoing and each of the following embodiments, it is also to be understood that the formulae include and represent each possible isomer, such as stereoisomers and geometric isomers, both individually and in any and all possible mixtures. In each of the foregoing and each of the following embodiments, it is also to be understood that the formulae include and represent any and all crystalline forms, partially crystalline forms, and non crystalline and/or amorphous forms of the compounds.
As used herein, the term “solvates” refers to compounds described herein complexed with a solvent molecule. It is appreciated that compounds described herein may form such complexes with solvents by simply mixing the compounds with a solvent, or dissolving the compounds in a solvent. It is appreciated that where the compounds are to be used as pharmaceuticals, such solvents are pharmaceutically acceptable solvents. It is further appreciated that where the compounds are to be used as pharmaceuticals, the relative amount of solvent that forms the solvate should be less than established guidelines for such pharmaceutical uses, such as less than International Conference on Harmonization (ICH) Guidelines. It is to be understood that the solvates may be isolated from excess solvent by evaporation, precipitation, and/or crystallization. In some embodiments, the solvates are amorphous, and in other embodiments, the solvates are crystalline.
In various aspects, the compounds of the present disclosure may also include one or more of the following compound structures:

Any of the compounds described herein, and their pharmaceutically acceptable salts or derivatives, may be prepared as a pharmaceutical formulation for systemic administration. Such pharmaceutical formulations and processes for making the same are known in the art for both humans and non-human mammals. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, (A. Gennaro, et al., eds., 19th ed., Mack Publishing Co., 1995). The pharmaceutical formulation may further comprise at least one additional active ingredient.
In various aspects, the compounds of the present disclosure are agonists of PPARδ. As used herein, the term “agonist” refers to the ability of a compound to interact with a receptor and evoke a maximal effect. This effect is known as the intrinsic efficacy. In contrast, “partial agonists” interact with a receptor but produce a less than maximal response. As used herein, the term “PPARδ” refers to the Peroxisomal Proliferator Activating Receptor beta or delta (PPAR-β or PPAR-δ), also known as NR1C2 (nuclear receptor subfamily 1, group C, member 2). In certain embodiments, the compounds have a specified binding affinity. As used herein, the term “binding affinity” has its generally accepted meaning in the art, for example a measure of the intrinsic binding strength of the reaction between the compounds and the PPARδ receptor. In some embodiments, the compound has a binding affinity between −10.0 and −12.0 kcal/mol.
In other embodiments, the compounds bind with an amino acid residue of the PPARδ binding pocket. As used herein, the term “binding pocket” refers to a region of a molecule or molecular complex (such as a receptor) that, as a result of its shape, favorably associates with another chemical entity or compound. In some embodiments, the amino acid residue is selected from the group consisting of Cys285, Thr288, Thr289, Leu330, Val334, Leu339, Leu353, and Phe368. In yet other embodiments, the binding between the compound and the amino acid residue is a hydrogen bond.
In various aspects, the compounds of the present disclosure are agonists of PPARγ. As used herein, the term “PPARγ” refers to the Peroxisomal Proliferator Activating Receptor gamma (PPAR-γ or PPARG), also known as the glitazone receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3). In certain embodiments, the compounds have a specified binding affinity. In some embodiments, the compound has a binding affinity between −10.0 and −12.0 kcal/mol.
In other embodiments, the compounds bind with an amino acid residue of the PPARγ binding pocket. In some embodiments, the amino acid residue is selected from the group consisting of Leu228, Cys285, Gln286, Arg288, Ser289, Glu295, Met329, Leu330, Ser342, Glu343, Phe363, and His 449. In yet other embodiments, the binding between the compound and the amino acid residue is a hydrogen bond.
In certain aspects, the compound is an agonist of PPARδ and an agonist of PPARγ. In other aspects, the compound permeates the blood-brain barrier. As used herein, the term “blood-brain barrier” has its generally accepted meaning in the art, such as the selective permeability barrier that separates the circulating blood from the brain extracellular fluid (BECF) in the central nervous system (CNS).
In various aspects of the present disclosure, methods are provided. In some embodiments, a method of treating diabetes mellitus in a patient in need thereof is provided. As used herein, the term “diabetes mellitus” has its generally accepted meaning in the art, such as a variable disorder of carbohydrate metabolism caused by a combination of hereditary and environmental factors and usually characterized by inadequate secretion or utilization of insulin, by excessive urine production, by excessive amounts of sugar in the blood and urine, and by thirst, hunger, and loss of weight. In some embodiments, the diabetes mellitus is Type 1 diabetes mellitus. In other embodiments, the diabetes mellitus is Type 2 diabetes mellitus.
In certain aspects, the methods include the step of administering a therapeutically effective amount of a composition to a patient. As used herein, the term “administering” refers to any suitable means of delivering the composition of the present disclosure the patient. In some embodiments, the administration is a parenteral administration. Suitable routes for such parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intradermal, epidural, intracerebroventricular, intraurethral, intrasternal, intracranial, intratumoral, intramuscular and subcutaneous delivery. Suitable means for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. In other embodiments, the administration is an oral administration. The term “oral administration” refers to the provision of a composition via the mouth through ingestion, or via some other part of the gastrointestinal system including the esophagus. Examples of oral dosage forms include tablets (including compressed, coated or uncoated), capsules, hard or soft gelatin capsules, pellets, pills, powders, granules, elixirs, tinctures, colloidal dispersions, dispersions, effervescent compositions, films, sterile solutions or suspensions, syrups and emulsions and the like.
As used herein, the term “therapeutically effective amount” refers to an amount which gives the desired benefit to a patient and includes both treatment and prophylactic administration. The amount will vary from one patient to another and will depend upon a number of factors, including the overall physical condition of the patient and the underlying cause of the condition to be treated. As used herein, the term “composition” can refer to any of the compounds described in the present disclosure. As used herein, the term “patient” refers to an animal, for example a human.
In some embodiments, the administration results in improvement of at least one symptom associated with diabetes mellitus in the patient. There are many symptoms associated with diabetes mellitus that are known in the art, for example: impaired insulin sensitivity, impaired glucose utilization, excessive thirst and appetite, increased urination, fatigue, nausea, vomiting, blurred vision, dry mouth, slow-healing sores or cuts, and itching skin.
In some embodiments, the method is associated with improved insulin sensitivity in the patient. As used herein, the term “insulin-sensitivity” refers to ability of a patient to reduce serum glucose levels in response to increased levels of insulin.
In other embodiments, the method is associated with improved glucose utilization in the patient. As used herein, the term “glucose utilization” refers to the absorption of glucose from the blood by muscle and fat cells and utilization of the sugar for cellular metabolism. The uptake of glucose into cells is stimulated by insulin.
In yet other embodiments, the method is associated with improved induction of mitochondrial biogenesis in the patient. The term “mitochondrial biogenesis” refers to processes of growth, amplification and healthy maintenance of the mitochondria.
In some embodiments, the method is associated with improved insulin signaling in the brain of the patient. Insulin signaling in the brain is a component of cognitive process in an animal, and can be monitored by any method known in the art.
In some embodiments, the method is not associated with lipid accumulation in the patient. Lipid accumulation refers to, for example, an increase in the level of total lipids, an increase in at least one type of fatty acid (e.g., very long chain fatty acids), or an increase in cholesterol or lipoproteins (e.g., chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL)). In other embodiments, the method does not induce an increase in lipid accumulation in the patient. In certain embodiments, the lipid accumulation is ectopic lipid accumulation. Ectopic lipid accumulation refers to lipid accumulation in non-adipose tissue and is believed to be an important consideration in diabetes management.
In other embodiments, the method is not associated with adverse cardiovascular event in the patient. As used herein, the term “adverse cardiovascular event” refers, generally, to a disorder or disease of the cardiovascular system resulting from progressive vascular damage. Although the event may have a rather sudden onset, it can also refer to a progressive worsening of such a disorder or disease. Examples of cardiovascular events include, without limitation: claudication, cardiac arrest, myocardial infarction, ischemia, stroke, transient ischemic attacks, worsening of angina, heart failure, congestive heart failure, or left ventricular hypertrophy. Examples of progressive vascular diseases are those that affect the cerebral, coronary, renal, or peripheral circulations. In one embodiment, the adverse cardiovascular event is heart failure. In another embodiment, the adverse cardiovascular event is myocardial infarction.
In other aspects, a method of treating Alzheimer's disease in a patient in need thereof is provided. The previously described embodiments of the method of treating diabetes mellitus in a patient are applicable to the method of treating Alzheimer's disease in a patient described herein.
In some embodiments, the method is associated with improvement of a cognitive deficit in the patient. The term “cognitive deficit” may include one or more of the following: loss of or important deterioration in short-term and/or long-term memory or loss of or important deterioration in learning ability, loss of executive functions (rational decision making, judgment), decline in the ability to carry out activities of daily living, personality changes, and hallucinations or delusions. Cognitive decline in learning means significantly prolonged period of time required to acquire new skills or information, and a decline in memory means significantly shortened periods for retaining such skills or information. In certain embodiments, the cognitive deficit is memory impairment. Methods to evaluate cognitive deficit can be performed according to known methods in the art.
In other embodiments, the method is associated with an improvement in cognition in the patient. The term “cognition” as used herein refers to the mental process of knowing, including aspects such as awareness, perception, reasoning, and judgment. It may also be referred to as the operation of the mind by which one becomes aware of objects of thought or perception, including all aspects of perceiving, thinking, and remembering. Methods to evaluate cognition can be performed according to known methods in the art.
In yet other embodiments, the method is associated with central PPARγ activation. The term “central PPARγ activation” refers to activation of PPARγ receptors in the central nervous system of the patient, for example in the brain of the patient. In some embodiments, the central PPARγ activation is in the hippocampus of the patient. Methods to evaluate central PPARγ activation can be performed according to known methods in the art.
In some embodiments, the method is associated with an improvement in synaptic plasticity in the patient. Synaptic plasticity refers to the cellular process that results in lasting changes in the efficacy of neuro-transmission. More specifically, it refers to the variability of the strength of a signal transmitted through a synapse. Methods to evaluate synaptic plasticity can be performed according to known methods in the art.
In other embodiments, the method is associated with a decrease in Tau phosphorylation in the hippocampus of the patient. Tau hyperphosphorylation represents a classic hallmark for the evidence of Alzheimer's disease due to the involvement of Tau in microtubule disassembly and neuronal degeneration. The mechanism underlying the Aβ-induced Tau hyperphosphorylation as mediated by impaired insulin signal transduction has been delineated, finding that pAKT and GSKp upon insulin stimulation was compromised under Aβ conditions. Furthermore, in post mortem Alzheimer's brain, reduced mediators have been found in the insulin signaling cascade including the insulin receptor, insulin receptor substrate (IRS-1), and the pro-survival protein AKT. Methods to evaluate Tau phosphorylation can be performed according to known methods in the art.
In yet other embodiments, the method is associated with a decrease in PTEN expression in the hippocampus of the patient. The term “PTEN” refers to the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10. PTEN acts as a tumor suppressor gene through the action of its phosphatase protein product, which is involved in the regulation of the cell cycle. Methods to evaluate PTEN expression can be performed according to known methods in the art.
In certain embodiments, the method is associated with an increase in BDNF expression in the hippocampus of the patient. The term “BDNF” refers to brain-derived neurotropic factor, a member of the “neurotrophin” family of growth factors found in the brain and the periphery of patients. BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons and encourage the growth and differentiation of new neurons and synapses. In the brain, it is active in the hippocampus, cortex, and basal forebrain, and is important for long-term memory. Methods to evaluate BDNF expression can be performed according to known methods in the art.
In other aspects, a method of improving insulin sensitivity in a patient is provided. The previously described embodiments of the method of treating diabetes mellitus in a patient are applicable to the method of improving insulin sensitivity described herein.
In various aspects, method of improving glucose utilization in a patient is provided. The previously described embodiments of the method of treating diabetes mellitus and the method of improving insulin sensitivity are applicable to the method of improving glucose utilization described herein.
In certain aspects, a method of improving a cognitive deficit in a patient is provided. The previously described embodiments of the method of treating Alzheimer's disease are applicable to the method of improving a cognitive deficit in a patient described herein.
In other aspects, a pharmaceutical formulation comprising a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or derivative thereof, and one or more pharmaceutically acceptable carriers is provided. The previously described embodiments of the compounds are applicable to the pharmaceutical formulations described herein. “Compound 9,” “Compound 3-91,” “Compound 4-23,” and “Compound 3-121,” and their pharmaceutically acceptable salts or derivatives, may be prepared as a pharmaceutical formulation for systemic administration. Such pharmaceutical formulations and processes for making the same are known in the art for both humans and non-human mammals. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, (A. Gennaro, et al., eds., 19th ed., Mack Publishing Co., 1995). The pharmaceutical formulation may further comprise at least one additional active ingredient.
As used herein, the term “carrier” means any ingredient other than the active component(s) in a formulation. The choice of carrier may depend on factors such as the particular mode of administration, the effect of the carrier on solubility and stability, and the nature of the dosage form.
In various embodiments, the pharmaceutical formulation is suitable for administration to a patient at a specified dose range. In one embodiment, pharmaceutical formulation is suitable for administration at a dose of about 0.001 to about 1000 mg of the compound per kg of patient body weight. In another embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 0.001 to about 100 mg of the compound per kg of patient body weight. In yet another embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 0.01 to about 100 mg of the compound per kg of patient body weight. In one embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 0.1 to about 100 mg of the compound per kg of patient body weight. In another embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 0.1 to about 10 mg of the compound per kg of patient body weight. In yet another embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 1 to about 5 mg of the compound per kg of patient body weight. In one embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 2 mg of the compound per kg of patient body weight. In another embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 3 mg of the compound per kg of patient body weight. In yet another embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 4 mg of the compound per kg of patient body weight. In another embodiment, the pharmaceutical formulation is suitable for administration at a dose of about 5 mg of the compound per kg of patient body weight.
While the invention is susceptible to various modifications and alternative forms, specific embodiments are herein described in detail. It should be understood, however, that there is no intent to limit the invention to the particular forms described, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the scope of the invention.